Please use this identifier to cite or link to this item: http://doi.org/10.25358/openscience-6366
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dc.contributor.authorAslam, Muhammad-
dc.contributor.authorKandasamy, Nirosiya-
dc.contributor.authorUllah, Anwar-
dc.contributor.authorParamasivam, Nagarajan-
dc.contributor.authorÖztürk, Mehmet Ali-
dc.contributor.authorNaureen, Saima-
dc.contributor.authorArshad, Abida-
dc.contributor.authorBadshah, Mazhar-
dc.contributor.authorKhan, Kafaitullah-
dc.contributor.authorWajid, Muhammad-
dc.contributor.authorAbbasi, Rashda-
dc.contributor.authorIlyas, Muhammad-
dc.contributor.authorEils, Roland-
dc.contributor.authorSchlesner, Matthias-
dc.contributor.authorWade, Rebecca C.-
dc.contributor.authorAhmad, Nafees-
dc.contributor.authorEngelhardt, Jakob von-
dc.date.accessioned2021-09-24T09:24:57Z-
dc.date.available2021-09-24T09:24:57Z-
dc.date.issued2021-
dc.identifier.urihttps://openscience.ub.uni-mainz.de/handle/20.500.12030/6376-
dc.description.abstractRare variants in the beta-glucocerebrosidase gene (GBA1) are common genetic risk factors for alpha synucleinopathy, which often manifests clinically as GBA-associated Parkinson’s disease (GBA-PD). Clinically, GBA-PD closely mimics idiopathic PD, but it may present at a younger age and often aggregates in families. Most carriers of GBA variants are, however, asymptomatic. Moreover, symptomatic PD patients without GBA variant have been reported in families with seemingly GBA-PD. These observations obscure the link between GBA variants and PD pathogenesis and point towards a role for unidentified additional genetic and/or environmental risk factors or second hits in GBA-PD. In this study, we explored whether rare genetic variants may be additional risk factors for PD in two families segregating the PD-associated GBA1 variants c.115+1G>A (ClinVar ID: 93445) and p.L444P (ClinVar ID: 4288). Our analysis identified rare genetic variants of the HSP70 co-chaperone DnaJ homolog subfamily B member 6 (DNAJB6) and lysosomal protein prosaposin (PSAP) as additional factors possibly influencing PD risk in the two families. In comparison to the wild-type proteins, variant DNAJB6 and PSAP proteins show altered functions in the context of cellular alpha-synuclein homeostasis when expressed in reporter cells. Furthermore, the segregation pattern of the rare variants in the genes encoding DNAJB6 and PSAP indicated a possible association with PD in the respective families. The occurrence of second hits or additional PD cosegregating rare variants has important implications for genetic counseling in PD families with GBA1 variant carriers and for the selection of PD patients for GBA targeted treatments.en_GB
dc.language.isoengde
dc.rightsCC BY*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.subject.ddc610 Medizinde_DE
dc.subject.ddc610 Medical sciencesen_GB
dc.titlePutative second hit rare genetic variants in families with seemingly GBA-associated Parkinson’s diseaseen_GB
dc.typeZeitschriftenaufsatzde
dc.identifier.doihttp://doi.org/10.25358/openscience-6366-
jgu.type.dinitypearticleen_GB
jgu.type.versionPublished versionde
jgu.type.resourceTextde
jgu.organisation.departmentFB 04 Medizinde
jgu.organisation.number2700-
jgu.organisation.nameJohannes Gutenberg-Universität Mainz-
jgu.rights.accessrightsopenAccess-
jgu.journal.titlenpj Genomic Medicinede
jgu.journal.volume6de
jgu.pages.alternative2de
jgu.publisher.year2021-
jgu.publisher.nameNature Publ. Groupde
jgu.publisher.placeLondonde
jgu.publisher.urihttps://doi.org/10.1038/s41525-020-00163-8de
jgu.publisher.issn2056-7944de
jgu.organisation.placeMainz-
jgu.subject.ddccode610de
jgu.publisher.doi10.1038/s41525-020-00163-8
jgu.organisation.rorhttps://ror.org/023b0x485
Appears in collections:JGU-Publikationen

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